1824 | A. D. Jacobson et al. Molecular Biology of the Cell MBoC | ARTICLE Autoregulation of the 26S proteasome by in situ ubiquitination

ABSTRACT The 26S proteasome degrades ubiquitinated proteins, and proteasomal degra-dation controls various cellular events. Here we report that the human 26S proteasome is ubiquitinated, by which the ubiquitin receptors Adrm1 and S5a, the ATPase subunit Rpt5, and the deubiquitinating enzyme Uch37 are ubiquitinated in situ by proteasome-associating ubiquitination enzymes. Ubiquitination of these subunits significantly impairs the 26S protea-some’s ability to bind, deubiquitinate, and degrade ubiquitinated proteins. Moreover, ubiq-uitination of the 26S proteasome can be antagonized by proteasome-residing deubiquitinat-ing enzymes, by the binding of polyubiquitin chains, and by certain cellular stress, indicating that proteasome ubiquitination is dynamic and regulated in cells. We propose that in situ ubiquitination of the 26S proteasome regulates its activity, which could function to adjust proteasomal activity in response to the alteration of cellular ubiquitination levels